Fehlbildungen des Herzens, der großen Arterien, Gefäßbildung Medizinische Embryologie, 2015/2016, II. Semester Fehlbildungen des Herzens, der großen Arterien, Gefäßbildung dr. Attila Magyar 05.03.2016

Gefäßbildung Blutinseln: Dottersack, extraembryonal Gefäßbläschen: Vaskulogenesis, intraembryonal Verlängerung und Fusion dieser Bläschen: Bildung eines Netzwerks Angiogenesis: Ausstülpung neue Gefäße aus den schon existierenden Gefäßen

Blutinseln

Bildung der Blutzellen und Blutgefäßen aus Blutinseln McGeady, Quinn, FitzPatrick, Ryan, VETERINARY EMBRYOLOGY, Blackwell, 2006 Bildung der Blutzellen und Blutgefäßen aus Blutinseln

Hämangioblast: mesenchymale Stammzelle für Blutbildung und Endothelbildung Bildung der Blutinseln im Mensch: von ET17, zuerst extraembryonal (in der Dottersackwand) Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009)

Fusion der Blutinseln zu Netzwerken von Blutgefäßen Hinrichsen, Human Embryologie, Springer, 1990

Vaskulogenesis

Vaskulogenesis beginnt ab E18 intraembryonal ohen Blutzellbildung (nur de novo Gefäßbildung), d.h. nur Angioblasten oder Endothel Vorläuferzellen (EPC) EPC entstehen nur in der Splanchnopleura Somitopleura: EPCs wandern hinein

Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009) Ursprung der Gefäßbildenden Stammzellen: die meiste Angioblasten (EPC: endothelial precursos cells) stammen aus Splanchnopleura (rot), aber werden solche Stammzelle auch in dem paraxialen Mesoderm entstanden. Diese letztere können in verschiedenen Regionen einmigrieren, so ist es möglich, daß die Aorte ventral aus splanchnopleuralen Endothelzellen, doersal aus paraxialen besteht.

passiert in der intraembryonalen Splanchnopleura Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009) Vaskulogenesis: passiert in der intraembryonalen Splanchnopleura

The primitive vascular network established through vasculogenesis is expanded and remodeled by angiogenesis. Expansion by angiogenesis occurs by sprouting from existing vessels or by intussusception, a splitting of existing vessels. Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009) Angiogenesis: neue Gefäe können durch Ausstülpung (sprouting) oder durch Zweiteilung (intussusception) der schon existierenden Gefäßen entstehen.

Intussusceptive angiogenesis Intussusceptive angiogenesis. A, B, Drawings illustrating the basic steps of intussusceptive angiogenesis. It begins with the protrusion of opposing capillary endothelial cells (EC) into the lumen. At the point of contact, the endothelial layer and basement membrane (BM) is perforated and invaded by pericytes (Pr, capillary supportive cells) and interstitial fibroblasts (Fb) while the epithelial lining of the newly formed capillaries is reconstituted. Co, collagen. Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009) Angiogenesis mit Intussusception (Co: Kollagenfasern, Fb: Fibroblast, grün: Endothelzelle, Pr: Perizyt, BM: Basalmembran)

An diesen Bildern sieht man den Vorgang der Intussusception, Abschnürung eines Gefäßes von einem Netztwerk schon existierenden Gefäßchen. Scanning electron micrograph showing branching of chick chorioallantoic membrane vessels by intussusception. A, Perforations and pillars penetrate into existing vessels and bridge across the vessel lumen (arrows). B, C, Pillars then lengthen and merge (arrowheads) and eventually sever and separate the vessel (curved arrows) from the underlying capillary bed. Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009)

Pardali TICB, 2010

Hypothesized model for establishing arterial and venous identity and for the remodeling leading to the formation of two separate types of vessels. Notch signaling (by repressing the expression of the venous phenotype) and Tgf!/Alk1 signaling both promote the expression of arterial markers in endothelial precursor cells, possibly instilling an arterial identity to these cells before they assemble primitive vessels. This leads to the expression of EphrinB2 in arterial cords and EphB4 in the venous cords, which is ultimately responsible for segregating the two vessel groups. In this model, Ang/Tie signaling serves to stabilize these vessels and regulate their maturation. Angiogenic growth (mediated by Vegf/Nrp1 signaling in arterial beds and Vegf/Nrp2 signaling in venous beds) and remodeling then sculpts these vascular beds into their final configurations.

Blutzellenbildung: Hämatopoese mit verschiedenen Phasen: Dottersack Phase (erste, von hier wird die erste Besiedlung der Leber stattfinden) 1. hepatische Phase (um 23 ET) Aorta-Gonad-Mesonephros (AGM) Region, von hier wird Leber zweitemal besiedelt (um ET30: Adult-Type Hämopoese) Knochenmark-Phase ab EW10,5, aber Leber bleibt bis Geburt die Hauptstelle der Blutzellbildung. Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009)

Blutbildung in der AGM-Region: in dem splanchnopleuralen Mesenchym von Aorte, Gonaden, Mesonephros Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009)

Hämopoetische Stammzellen in der Aortenwand: A: 3-Tage-altes Kükenembryo, Immunhistoichemie für CD41 B: ET10 Mausembryo mit CD41 C: junges Schweinembryo (Zeichnung) D: ET35 menschliches Embryo mit anti-CD45 Larsen’s Human Embriology (4E, Schoenwolf, Bleyl, Brauer, Francis-West, Churchill-Livingstone, 2009)

Fetaler Blutkreislauf

Ductus arteriosus und venosus im menshclichen Embryo Ductus arteriosus und venosus im menshclichen Embryo. Die Zahlen bedeuten die Sauerstoffsättigung des Blutes.

Genetische Mutationen, die Herzfehler verursachen können

1 Principles of developmental genetics, Sally E. Moody, Academic Press 2007

2 Principles of developmental genetics, Sally E. Moody, Academic Press 2007

3 Principles of developmental genetics, Sally E. Moody, Academic Press 2007

4 Principles of developmental genetics, Sally E. Moody, Academic Press 2007

Principles of developmental genetics, Sally E Principles of developmental genetics, Sally E. Moody, Academic Press 2007

Kongenitale Herzfehler Eingeteilt in drei Gruppen (Bruneau, Nature, 2006): zyanotische Herzfehler (Herzvitien; Vitium, Vitia: Fehler) Linksherzobstruktionen Septierungsdefekte

I. Zyanotische Herzfehler Blaue Babys: sauerstoffreiches und –armes Blut wird gemischt Einige Beispiele: TGA (Transposition der großen Gefäßen) TOF (Tetralogy of Fallot) PTA (Persistierender Truncus arteriosus) DORV (Double outlet right ventricle) TAPVC (Totale Lungenvenenfehlmőndung) EA (Ebstein-Anomalie)

II. Linksherzobstruktionen HLHS (hypoplastisches Linksherz Syndrom) MS (mitrale Stenose) AS (Aortenstenose) CA (Coarctatio aortae)

III. Septierungsdefekten ASD (Vorhofseptumdefekten) VSD (Ventrikelseptumdefekten) AVSD (Vorhof-Ventrikelseptumdefekten)

IV. Andere, nicht eingeteilte Kategorien BAV (bikuspidale Aortenklappe) PDA (Patent Ductus Arteriosus) ccTGA (congenitally corrected transposition of the great arteries)

Häufigkeit der Herzfehler Bruneau, Nature 2006

I. Zyanotische Herzfehler

TGA

Transposition of great arteries (TGA) Assoziiert häufig mit Mutationen (Mensch): NKX2-5 THRAP2

Önbas, Diagnostic and Interventional Radiology

The free wall of the right atrium and right ventricle, along with the anterior aspect of the aorta have been removed in this heart with transposition of the great arteries. The pulmonary trunk is posterior and to the left of the aorta. The aorta is stenotic and is supported by a complete muscular infundibulum. Distally, there is a severe aortic coarctation with narrowing of the isthmus between the left common carotid artery (LCCA) and the patent arterial duct. There are concordant atrioventricular connections and a non-committed, muscular ventricular septal defect. (SCV-superior caval vein, BCT-brachiocephalic trunk, LSA-left subclavian artery) http://www.accd-awg.umn.edu/Transposition/TGA_VSD_COA_01_05_01/ACHA94_19b.html

A close up view of the heart shown in the left panel with the anterior portion of the aortic valve (AV) opened to demonstrate the discordant atrioventricular connections consistent with transposition of the great arteries. The aorta is anterior to the pulmonary trunk with a pulmonary artery (PA) band in place. The right coronary orifice (RCO) is adjacent to a commissure. Note the muscular infundibulum separating the aortic valve from the tricuspid valve (TV). (RA-right atrium) http://www.accd-awg.umn.edu/Transposition/TGA_IVS_01_01_02/TGA_IVS_01_01_02.html

The discordant ventriculo-arterial connections are easily seen on the left, with the mitral valve guarding the inlet and the pulmonary trunk forming the outlet component of the morphologically left ventricle. Note the fibrous continuity between the atrioventricular and arterial valves. There is a substantial remnant of the membranous septum at the roof of the perimembranous ventricular septal defect. (Van Mierop Archive – University of Florida, Gainesville, FL) http://www.accd-awg.umn.edu/Transposition/TGA_VSD_01_05_01/TGA4d.html

TOF

http://health.allrefer.com/pictures-images/tetralogy-of-fallot.html

Fallot’sche Tetralogie: assoziiert mit Mutationen: NKX2-5 NOTCH1 TBX1 JAG1 NOTCH2 http://www.inova.org/healthcare-services/pediatrics/types-of-services/pediatric-cardiovascular-program/procedures/systemic-to-pulmonary-shunt.jsp

http://www. doctortipster http://www.doctortipster.com/3146-tetralogy-of-fallot-symptoms-diagnosis-and-treatment.html

This subcostal long axis view of the right ventricle (RV) demonstrates the anterior deviation of the outlet septum (*), causing the infundibular pulmonary stenosis associated with tetralogy of Fallot. There is also supravalvar pulmonary stenosis with dilatation of the pulmonary trunk (PT). The aorta (A) overrides the interventricular septum in this heart with an atrioventricular septal defect (not shown). (SCV-superior caval vein, RA-right atrium) http://www.accd-awg.umn.edu/TOF/TOF_AVC_01_01_20/TOF_AVC_01_01_20.html

A deeper cut into the right ventricle (RV) of the heart shown in TOF1a, shows the common atrioventricular valve (AVV). The left (L) component of the common atrioventricular valve is most posterior, the anterior portion resected and demonstrating the inferior (IBL) and superior (SBL) bridging leaflets as they cross the crest of the interventricular septum (yellow dots). The aorta (A) overrides the interventricular septum and the outlet septum is deviated anteriorly causing the infundibular pulmonary stenosis characteristic of tetralogy of Fallot. Please note the fibrous continuity between the aortic valve and the superior bridging leaflet   http://www.accd-awg.umn.edu/TOF/TOF_AVC_01_01_20/TOF1b.html

http://www.ipccc-awg.net/Pulmonary_Atresia/PA_Atresia_TOF/TOF3b.html

Clubbing fingers, a common sign of TOF Wikipedia

PTA

En: Persistent Truncus Arteriosus (PTA) De: Truncus arteriosus communis assoziiert mit Mutationen in TBX1

Fig. 2: MIP (Fig. 2) and VRT (Fig Fig.2: MIP (Fig. 2) and VRT (Fig. 3) images demonstrate the arterial trunk which divides into the aorta and main pulmonary artery, and the main pulmonary artery subsequently divides into the left and right branch pulmonary arteries. Volumen rendering technique (VRT), Maximum intensity projection MIP http://health.siemens.com/ct_applications/somatomsessions/index.php/diagnosis-of-truncus-arteriosus-using-flash-ct-scanning/

Fig. 3: MIP (Fig. 2) and VRT (Fig Fig.3: MIP (Fig. 2) and VRT (Fig. 3) images demonstrate the arterial trunk which divides into the aorta and main pulmonary artery, and the main pulmonary artery subsequently divides into the left and right branch pulmonary arteries. http://health.siemens.com/ct_applications/somatomsessions/index.php/diagnosis-of-truncus-arteriosus-using-flash-ct-scanning/

TAPVR

Total anomalous pulmonary venous return (TAPVR)

Fig. 1. Preoperative cardiac computerized tomography showing supracardiac total anomalous pulmonary venous drainage which was draining to the junction between the right SVC and the right atrium. LPA, left pulmonary artery; LUPV, left upper pulmonary vein; LLPV, left lower pulmonary vein; RSVC, right superior vena cava; DV, draing vein; RPA, right pulmonary arteryt; RUPV, right upper pulmonary vein; RLPV, right lower pulmonary vein. Interactive CardioVascular and Thoracic Surgery 2008;7:282-284.

TAPVR: mögliche Variationen

DORV

http://www. childrenshospital http://www.childrenshospital.org/health-topics/conditions/double-outlet-right-ventricle-dorv

The right ventricle has been opened in a clam shell-like fashion, showing the tricuspid valve guarding the inlet and the origin of both arterial trunks from this double outlet right ventricle. There are bilateral, complete, muscular infundibulums (red asterisks) supporting each arterial trunk with absence of continuity between the leaflets of the arterial and atrioventricular valves. There is a non-committed, restrictive, muscular, inlet ventricular septal defect. Note the coarse trabeculations within this morphologically right ventricle. http://www.accd-awg.umn.edu/DORV/DORV_VSD/DORV_VSD_MA/CMAUN-T80b.html

This view of the septal surface and the outlet components of this double outlet right ventricle illustrates the aorta anterior and to the right of the pulmonary trunk with anterior deviation of the outlet septum (*). This arrangement is similar to that of tetralogy of Fallot with pulmonary stenosis secondary to the anterior deviation of the outlet septum. There is a subaortic ventricular septal defect with a posterior, inferior muscular rim separating the aortic valve from the tricuspid valve (TV). The single coronary orifice (CO) gives rise to a single coronary artery. http://www.accd-awg.umn.edu/DORV/DORV_TOF/DORV2a.html

ccTGA

Congenitally Corrected Transposition of the Great Arteries Chang, AJR 2007; 188:W428–W430 Congenitally Corrected Transposition of the Great Arteries Three-dimensional volume-rendered image shows spatial relationship of great arteries with ascending aorta anterior and to left of main pulmonary artery. Anterior descending artery (short arrow) and circumflex artery (arrowhead) arise from common left ventricular coronary artery off of anterior aortic sinus. Right coronary artery (long arrow) arises from posterior aortic sinus. Chang, AJR 2007; 188:W428–W430

This dissection is made to replicate the parasternal long echocardiographic projection. It shows the coronary sinus (CS) opening to the right-sided morphologically right atrium, which connects to the morphologically left ventricle (mLV) through the mitral valve (MV). The oval fossa (OF) is clearly seen in the atrial septum

This illustration demonstrates how the morphologically right atrium, with its characteristic appendage (RAA), is connected to a morphologically left ventricle (mLV) across the mitral valve (MV), with the ventricle then connected to the pulmonary trunk (PT). Note the smooth septal surface of the ventricle.

Note the reversed off-setting of the attachments of the leaflets of the atrioventricular valves to the septum (Arrow), with the mitral valve (MV) on the right side attached appreciably higher that the tricuspid valve (TV) on the left side.

This illustration demonstrates the apical displacement (lines) of the septal and mural leaflets of the tricuspid valve (TV). The morphologically left atrium (mLA) is connected to the morphologically right ventricle (mRV) through an Ebstinoid-like tricuspid valve. Note the flap valve of the oval fossa on the atrial septal surface.

Congenitally corrected transposition oder L-Transposition (geht zusammen mit AV-Block) Images from ECG-gated CT scan of 52-year-old woman with dextrocardia, situs inversus, and congenitally corrected transposition of great arteries (TGA). Volume-rendered image from anterior view provides 3D perspective of relationships of cardiac chambers and great vessels. Aortic valve is superior and to right of pulmonic valve, as expected with D-TGA. Pulmonary artery (P) is enlarged in this patient due to pulmonary arterial hypertension that is likely secondary to tricuspid valve disorder. Even though patient has situs inversus, anterior descending coronary artery (arrowheads) is supplied by left coronary artery (arrow) because ventricles are in D-loop configuration. LA = morphologic left atrium, LV = morphologic left ventricle, RA = morphologic right atrium, RV = morphologic right ventricle, SVC = superior vena cava. Am. J. Roentgenol. Maldjian and Saric 188 (6) S39

CA

32 year old pregnant patient with hypertension. http://radiopaedia.org/cases/coarctation-of-the-aorta-7 32 year old pregnant patient with hypertension. On examination patient had weak lower limb pulses. Oblique sagittal TRUFI image reveals post subclavian coarctation of aorta.

Leschka, RadioGraphics, 2007, 27: 829-846   Coarctation of the aorta at nongated CT in a 25-year-old man with atypical chest pain. Thin-section volume-rendered image, obtained with reconstruction in an oblique left-posterior plane by using the cut-plane mode, demonstrates narrowing of the aortic isthmus (small arrow) and extensive collateral intercostal and nuchal arteries (large arrow).

Septumdefekten

Atrial septal defect (fossa ovalis type) (Ostium secundum Defekt: zu gross ist das O. Sec)

Atrial septal defect (atrioventricular septal)

Patent foramen ovale (PFO): bis 30% der gesunden Bevölkerung! (aber: stroke und migraine)

Ventricular septal defect (membranous type)

Ventricular septal defect (muscular type)